Catheterization and Cardiovascular Diagnosis 41:79–84 (1997)

Basic Investigations

Reduction of Femoral Artery Bleeding

Post Catheterization Using
a Collagen Enhanced Fibrin Sealant
Jeanne K. Falstrom,1 MA, Norman C. Goodman,1 BS, Gursel Ates,2 MD,
Robert D. Abbott,3 PhD, Eric R. Powers,2 MD, and William D. Spotnitz,1* MD
As the number of cardiac catheterization procedures increases, so do associated
complications and costs. This study suggests that the application of a new collagen
enhanced fibrin sealant, Collasealt, may be used effectively to achieve rapid hemostasis
at the arterial puncture site following femoral artery catheterization. Results in nine dogs
anticoagulated with heparin (activated clotting time 396 6 107, mean 6 S.D.) revealed a
statistically significant reduction in signs of gross bleeding in the sealant-treated groins
as compared to control (2 versus 9, P 5 .0156). These results indicate that this
commercially produced sealant might be used in human patients undergoing cardiac
catheterization to decrease complications, lengths of stay, and costs. Cathet. Cardiovasc.
Diagn. 79–84, 1997. r 1997 Wiley-Liss, Inc.

Key words: tissue adhesive; hemostasis; groin; percutaneous

INTRODUCTION complication) being the most frequent problem [8].

Cardiac catheterization procedures have become an
integral tool in diagnosing and treating cardiovascular
disease. In 1991, an estimated 1 million procedures were
performed in U.S. nonfederal short-stay hospitals alone, a
figure which does not include the growing number of
outpatient/ambulatory catheterization procedures, esti-
mated at 12 percent of all such procedures in 1988. In
addition, total charges for in-hospital cardiac catheteriza-
tions averaged $10,880 in 1992, up from an average of
less than $5,000 in 1988. Hospital charges accounted for
82% of this total, with the length of stay averaging 4 days
in 1992, up from 2.8 in 1988 [1,2]. As these numbers
increase, so do efforts to facilitate and improve the
catheterization procedure to render it safer, more effi-
cient, and less costly for both patient and careprovider.
Manual compression is conventionally used for twenty
min to obtain initial hemostasis following femoral artery
catheterization. This method typically demands that pa-
tients remain immobilized with the groin compressed by
a weight or mechanical device for a minimum of 4–6
additional hours in order to ensure adequate hemostasis.
Not only does this requirement increase the time and
discomfort involved for the patient, but it also tends to
increase costs associated with the procedure by making
its performance on an outpatient basis difficult. While
there are currently efforts being made to increase the
number of outpatient procedures using the conventional
compression method [9,10], a new method of achieving
1Division of Thoracic and Cardiovascular Surgery, University of

One main area of focus has been to explore alternative
methods of achieving hemostasis safely and more effi-
ciently at the arterial puncture site following catheter
removal. The most common complications of percutane-
ous interventional cardiac procedures have been attrib-
uted to hemorrhage at the site of catheterization [3,4]. Of
the total number of patients undergoing these procedures,
the complication rate averages about 1% [3–7], with
hematoma (0.9% of total, or 90% of those suffering
Virginia Health Sciences Center, Charlottesville, Virginia
2Division of Cardiology, University of Virginia Health Sciences
Center, Charlottesville, Virginia
3Division of Biostatistics, University of Virginia Health Sciences
Center, Charlottesville, Virginia
*Correspondence to: William D. Spotnitz, M.D., Department of
Surgery, University of Virginia Health Sciences Center, P.O. Box
10005, Charlottesville, VA 22906-0005.
Received 6 September 1996, Revision accepted 3 December 1996

r 1997 Wiley-Liss, Inc.

80 Falstrom et al.
safe and rapid hemostasis with reduced complications
would allow earlier mobilization. More rapid mobiliza-
tion might permit more outpatient procedures which have
been found to cut costs [11–13] as well as ease patient
anxiety and discomfort [14,15]. A new hemostatic tech-
nique might also eliminate the need to reverse hepariniza-
tion at the end of the catheterization which can lead to
coronary arterial thrombosis.
Of the alternative methods being explored, some
involve using a collagen plug device to seal the arterial
puncture site. Collagen has a long history of surgical use
for its hemostatic properties [16–18]. For this application,
several different collagen plug devices have been devel-
oped and investigated in extensive laboratory and clinical
trials over the past several years [19–30]. More recently,
the application of fibrin sealant has been considered as a
method for sealing arterial puncture sites. This biological
tissue adhesive combines fibrinogen and thrombin to
form fibrin. Fibrin sealant shares with collagen its exten-
sive clinical use as a hemostatic and sealing agent in a
wide variety of applications [31–42]. A previous study
has suggested the potential of fibrin sealant for success-
fully sealing femoral artery catheterization sites [43]. In
this new study, we evaluated the effectiveness of an
investigational product, specifically, fibrin sealant en-
hanced with collagen, Collasealt (Cohesion, Palo Alto,
CA), for sealing arterial puncture sites. We hypothesized
that by applying this combined agent percutaneously
following femoral artery catheterization, safe and rapid
hemostasis may be achieved even in a heparinized model.
MATERIALS AND METHODS
Animal Preparation
This study employed a canine model to evaluate the
efficacy and safety of fibrin sealant enhanced with
collagen to seal arterial puncture sites following femoral
artery catheterization. All dogs were treated in accor-
dance with the ‘‘Position of the American Heart Associa-
tion on Research Animal Use.’’ The study group consisted
of nine adult mongrel dogs (30.3 6 7.0 kg) anticoagu-
lated with heparin. The dogs were administered general
anesthesia intravenously using Nembutal (30 mg/kg IV to
effect) (Abbott Laboratories, North Chicago, IL), and
were intubated and ventilated mechanically with a dual-
phase control respirator pump (Model 613, Harvard
Apparatus, Dover, MA). Additional Nembutal was admin-
istered as needed to maintain anesthesia. In order to
achieve venous access, catheters were placed in the
foreleg (20-gauge catheter, Critikon, Johnson & Johnson,
Tampa, FL) and in the external jugular vein (16-gauge
catheter, Critikon, Johnson & Johnson). Normal saline
was administered intravenously over the course of the
study to keep the dogs sufficiently hydrated. For the
purpose of the study, both femoral arteries were cannu-
lated with size 8F introducers and sheaths (Hemaquet II,
6468, USCI, Tewksbury, MA). 30 min were allowed to
pass prior to any efforts to remove the sheaths. The dogs
were anticoagulated with systemic doses of heparin
chosen and administered every 10 min to maintain an
elevated activated clotting time (ACT) from 350 to 400
with a mean of 396 6 107 (mean 6 S.D.) using a
previously published algorithm [44].
Composition and Preparation of Fibrin Sealant
Enhanced With Collagen
This adhesive is a composite of fibrinogen and throm-
bin derived from human-pooled, purified, and virally
inactivated sources enhanced with bovine Type I colla-
gen. Each application involves the preparation of two
separate components. The first component consists of a
60 mg/ml fibrinogen mixture with fibrinogen and colla-
gen as the main constituents, plus trace amounts of Factor
XIII and fibronectin. The second component consists of
50 U/ml thrombin in a 40 mM calcium chloride solution.
The two components are designed for application approxi-
mately 5–10 sec following their mixture in the delivery
system.
Delivery of Adhesive and Observation
The fibrin sealant enhanced with collagen was deliv-
ered to the soft tissue space adjacent to the arteriotomy in
order to obtain adequate hemostasis at the puncture site.
An identical catheter system was employed as was
described in detail and used in a previous study [43] in
order to avoid injecting the sealant into the artery. An
arterial sheath was linked to the adhesive administration
assembly via an introducer, which was positioned with its
tip entirely within the body of the sheath. The administra-
tion assembly contained two 5-ml syringes, one contain-
ing 3 ml of the fibrinogen/collagen component, the other
containing 3 ml of the thrombin component attached
using threeway luer lock stopcocks (Discofix, Burron
Medical Inc., Bethlehem, PA) to a single DuoFlo mixer
unit (Hemaedics, Inc. Malibu, CA). Also, attached to one
of the three-way stopcocks was a 10-ml syringe half-
filled with saline, which was observed in order to monitor
arterial blood pulsations to indicate the catheter tip
position. As the entire sheath and introducer assembly
was slowly withdrawn from the artery, the tip of the
sheath was considered to be in the soft tissues adjacent to
the artery when saline syringe pulsations ceased. At this
point, pressure was applied to the arterial puncture site,
the fibrin sealant enhanced with collagen was easily
immediately injected, the assembly was quickly with-
drawn, and manual pressure was increased and continued
for 20 min. The mixture was administered on one
randomly chosen side, with the other side left untreated as
 Hemostasis Using Collagen Enhanced Fibrin Sealant
a control. The control sheaths were removed in the same
fashion as for the treated side except that no adhesive was
instilled. After 20 min, manual compression was stopped
and both sides of the groin were observed for signs of
swelling or gross hemorrhage. Swelling was defined as
visible increasing soft tissue enlargement, and gross
hemorrhage was defined as active continuing blood loss.
Neither swelling nor hemorrhage would stop without
resuming manual compression. In the time frame chosen,
these two observations were the only local changes
detectable. Following 5 min observation, the dogs were
euthanised.
Statistics
Because this study uses the same animal for comparing
treated and control femoral arteries, McNemar’s test for
correlated proportions was chosen to evaluate the signifi-
cance of success of achieving hemostasis using the fibrin
sealant enhanced with collagen. Moreover, the limited
sample size meant that an asymptotic chi-square distribu-
tion could not be assumed when applying McNemar’s
test. Therefore, a Fisher-like exact test was employed to
assess statistical significance [45]. All hypothesis testing
was based on a .05 level of significance and was
two-sided.
RESULTS
Physical Signs
As seen in Table I, in this heparinized model all nine
control sides showed gross signs of bleeding, while only
two sealant-treated sides exhibited any evidence of
inadequate hemostasis (P 5 .0156) after completion of 20
min of manual compression. In none of the animals were
there indications of arterial occlusion or distal emboliza-
tion of the adhesive. There was no evidence of pallor or
cyanosis of the distal limb.
Exclusions
One experimental animal was excluded over the course
of ten experiments. This animal was accidentally injected
early in the experiment with a massive overdose of
Nembutal making it unsuitable for use. A total of nine
consecutive animals were consequently available for final
analysis.
DISCUSSION
Human Simulation
This model was intended to simulate complex cardiac
catheterization without heparin reversal in human pa-
tients. The catheters were left in place for at least 30 min
to mimic the amount of time necessary for complex
81
TABLE I. Observations in Heparinized Dogs*
P Value
Collagen enhanced (McNemar’s
fibrin sealant Control exact test)
GB 2 9 .0156
*Quantitative differences and statistical significance of findings in the
collagen enhanced fibrin sealant and control groins of heparinized dogs.
GB, gross bleeding.
catheterization. Similarly, groin pressure was applied for
20 min following catheter removal to achieve gross
hemostasis, as is done following human cardiac catheter-
ization. This investigational product has been designed
for use in humans as a commercial product and has been
virally inactivated in a series of steps involving solvent
detergent as a primary inactivator and heat as a secondary
inactivator. Moreover, the delivery system used has been
constructed to communicate with standard sheaths and
introducers currently in clinical use. The dogs remained
anticoagulated with systemic heparin, as are some human
patients at the time of complex catheterization, making
hemostasis even more difficult to obtain. The model
employed 8F sheaths to create a large arterial opening,
thereby increasing the difficulty of sealing the puncture
site.
Previous Investigation
Several different collagen plug devices for sealing
arterial puncture sites have been investigated in extensive
clinical trials. Though the mechanics of these devices
vary, they all work to position and secure a collagen plug
at the puncture site. These devices have been shown to be
generally successful in achieving rapid hemostasis even
in anticoagulated patients when deployed, with patients
ambulatory as little as 2 hr and even 30 min following
catheter removal [21,46].
Of the two different collagen plug systems currently
being investigated in clinical trials, one requires that two
successive plugs be delivered to seal the puncture site.
Unlike the collagen enhanced fibrin sealant administra-
tion assembly examined here, this collagen plug system
lacks a device to monitor consistently the position of the
application sheath relative to the femoral artery, increas-
ing the risk of inadvertently administering the two plugs
intra-arterially. One clinical study found a higher rate of
access site complications when comparing this device to
the conventional manual compression method, including
an increased incidence of femoral artery occlusions due
to intra-arterial placement of collagen material [27]. The
other collagen plug system currently under clinical inves-
tigation contains a relatively small amount of collagen in
comparison (6 16 mg vs. 6 180 mg) [29], but this system
requires an additional device to anchor the plug to the
82 Falstrom et al.
arterial wall. According to one clinical study, this anchor-
ing device failed to deploy properly in 3 out of 32
attempts (9%) [30]. In those patients where this failure
occurred, hemostasis was not achieved until conventional
manual pressure was used, or until a new collagen plug
system was employed and its anchoring device success-
fully engaged. In contrast, the assembly used to adminis-
ter fibrin sealant enhanced with collagen to seal arterial
puncture sites does not depend on the successful deploy-
ment of an anchoring device.
Fibrin sealant/collagen mixes have been successfully
employed to achieve hemostasis in other surgical applica-
tions [47,48]. A fibrin sealant enhanced with collagen can
be administered via the same mechanism as any other
fibrin sealant product, but it may create a more immedi-
ately stable longer-lasting plug due to the addition of
collagen. It is possible that such a longer-lasting plug
might cause local scar formation and increase difficulty of
future repeat arterial puncture. However, in this acute
study, clearly no observations of long-term changes were
made.
Comparison with Previous Fibrin Sealant
Investigation
This study documents a similar efficacy as compared to
a previous study which employed an identical model to
administer a fibrin sealant without collagen [43]. The
animals used in this study were heparinized to a larger but
similar extent as the animals in the earlier study (activated
clotting time of 396 6 107 compared to 374 6 22).
Moreover, a smaller volume of collagen enhanced fibrin
sealant was administered in this study, a mixture of 3 ml
collagen enhanced fibrinogen and 3 ml thrombin, as
compared to the 4 ml fibrinogen combined with 4 ml
thrombin [43]. Despite the smaller amount of adhesive in
this study and the small difference in heparinization of the
animals, the investigational product was effective at
controlling hemorrhage, as illustrated in Figure 1.
Practical Implications
This technique using fibrin sealant enhanced with
collagen might be applied in human patients to seal
arterial puncture sites following femoral artery catheter-
ization. The relatively brief time needed to achieve
hemostasis would allow earlier mobilization and would
consequently reduce the discomfort associated with ex-
tended compression methods and prolonged bed rest.
This technique might also enable cardiac catheterizations
to be performed more frequently on an outpatient basis by
reducing the need to hospitalize patients following cath-
eterization for observation and monitoring. By obtaining
rapid hemostasis even in heparinized subjects, this method
may reduce complications associated both with femoral
Fig. 1. Graph of gross bleeding observed in the groin area of
heparinized dogs following catheter removal and manual com-
pression. The graph documents reduced evidence of bleeding
in collagen enhanced fibrin sealant-treated dogs.
artery catheterization and with heparin anticoagulation
reversal.
Risks
The fibrin sealant enhanced with collagen system must
be employed with care in order to avoid inadvertently
administering the sealant intra-arterially, thereby causing
embolization. This complication can be avoided, how-
ever, by following the method described in this report to
confirm that the groin sheath is positioned outside the
femoral artery before instilling the sealant. In addition,
this agent, like other fibrin sealant products derived from
pooled sources of fibrinogen, does carry a risk of viral
disease transmission, at least theoretically. Both the
fibrinogen and the thrombin used in this product have
been virally inactivated by the manufacturer primarily by
solvent detergent and secondarily by heat. These methods
may reduce risks of viral contamination to less than one
in a billion. Finally, recent reports have suggested that
antibody production possibly producing significant abnor-
malities in coagulation might result from repeated expo-
sures to bovine thrombin [49]. The use of human
thrombin present in this investigational product elimi-
nates this danger. In addition, the bovine Type I collagen
used in this product is derived from a closed herd in order
to help minimize any risks of disease transmission.
Study Limitations
This study did not demonstrate a clear advantage for
collagen enhanced fibrin sealant over standard forms of
fibrin sealant [43] either because the sample size was
limited, because smaller volumes of sealant were used, or
because no significant difference exists.
 Hemostasis Using Collagen Enhanced Fibrin Sealant
The animals were observed for a period of only five
minutes following completion of compression. Clearly it
was not practical to allow the control side to keep
bleeding for longer than five minutes while continuing to
observe the fibrin sealant side for hemostasis. In addition,
this time was chosen because previous work has sug-
gested that once hemostasis is achieved on the fibrin
sealant side, it remains stable [43].
The animals were never mobilized following sealant
instillation and compression, so an evaluation of the
length of time before mobilization could not be per-
formed. In addition, the position of the introducer sheath
must be carefully determined before instilling the adhe-
sive in order to avoid injecting the sealant into the artery.
Work is currently being done to design a device to ensure
proper sealant application.
Although anticoagulation with heparin simulating cath-
eterization in humans was used in this study, pretreatment
with aspirin frequently used in the clinical setting was not
employed.
Finally, no studies currently exist comparing the use of
a fibrin sealant product to a collagen plug device for this
particular application [50]. Such a study might identify
more clearly what might be the advantages or disadvan-
tages of one method in relation to the other.
CONCLUSIONS
This study indicates that fibrin sealant enhanced with
collagen successfully prevents hematoma and gross hem-
orrhage in heparinized dogs upon femoral artery catheter
removal. These results suggest that this material might be
used safely and effectively in human patients following
femoral artery catheterization, and its routine application
might lessen patient complications, discomfort, and length
of hospitalization. Short- and long-term results in clinical
studies will need to be obtained in order to assess the
widespread safety and applicability of this technique.
ACKNOWLEDGMENTS
This work was sponsored in part by a grant from
Cohesion Corporation. Gursel Ates is a grant owner from
the Society of Turkish Cardiology, supported by Boeh-
ringer Ingelheim International.
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